Schizophrenia-related neural and behavioral phenotypes in transgenic mice expressing truncated Disc1.
Disrupted-in-Schizophrenia-1 (DISC1), identified by positional cloning of a balanced translocation (1;11) with the breakpoint in intron 8 of a large Scottish pedigree, is associated with a range of neuropsychiatric disorders including schizophrenia. To model this mutation in mice, we have generated Disc1(tr) transgenic mice expressing 2 copies of truncated Disc1 encoding the first 8 exons using a bacterial artificial chromosome (BAC). With this partial simulation of the human situation, we have discovered a range of phenotypes including a series of novel features not previously reported. Disc1(tr) transgenic mice display enlarged lateral ventricles, reduced cerebral cortex, partial agenesis of the corpus callosum, and thinning of layers II/III with reduced neural proliferation at midneurogenesis. Parvalbumin GABAergic neurons are reduced in the hippocampus and medial prefrontal cortex, and displaced in the dorsolateral frontal cortex. In culture, transgenic neurons grow fewer and shorter neurites. Behaviorally, transgenic mice exhibit increased immobility and reduced vocalization in depression-related tests, and impairment in conditioning of latent inhibition. These abnormalities in Disc1(tr) transgenic mice are consistent with findings in severe schizophrenia.
Shen
Sanbing
S
School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB252ZD, United Kingdom. sanbing.shen@abdn.ac.uk
Lang
Bing
B
Nakamoto
Chizu
C
Zhang
Feng
F
Pu
Jin
J
Kuan
Soh-Leh
SL
Chatzi
Christina
C
He
Shuisheng
S
Mackie
Iain
I
Brandon
Nicholas J
NJ
Marquis
Karen L
KL
Day
Mark
M
Hurko
Orest
O
McCaig
Colin D
CD
Riedel
Gernot
G
St Clair
David
D
D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000502:physiology*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000096:biosynthesis; D019417:Hindlimb Suspension / Q000379:methods; D007266:Inhibition, Psychological; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D016501:Neurites / Q000187:drug effects / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D010320:Parvalbumins / Q000378:metabolism; D010641:Phenotype; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D013550:Swimming
C498794:Disc1 protein, mouse; D009419:Nerve Tissue Proteins; D010320:Parvalbumins; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D001973:Bromodeoxyuridine